tbuckley/cabot-search huggingface dataset:
Abstract 4338: Response to neoadjuvant targeted therapy in operable head and neck cancer confers survival benefit
Authors: Marco Antonio Mascarella, Tolani Olonisakin, Purva Rumde, Varun Vendra, Melonie Nance, Seungwon Kim, Mark Kubik, Shaum Sridharan, Robert Ferris, Moon Fenton, Daniel Clayburgh, James Ohr, Malabika Sen, Sonali Joyce, James Herman, Jennifer Grandis, Dan Zandberg, Umamaheswar Duvvuri
Journal: Cancer Research (2023)

Abstract Purpose: Neoadjuvant targeted therapy provides a brief, preoperative ‘window of opportunity’ that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). Patients and Methods: A pooled analysis of treatment naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009-2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n=83) or anti-ErbB3 antibody therapy (n=9) within 28 days of surgery. Clinical to pathologic stage migration was compared to disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. Results: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared to a historic cohort without neoadjuvant therapy (P=0.048). Patients with pathologic downstage migration had the highest OS (89.5%, 95% CI 75.7-100) compared to those with no stage change (58%, 95% CI 46.2-69.8) or upstage (40%, 95% CI 9.6-70.4, P=0.003). On multivariable analysis, downstage migration remained a positive prognostic factor for OS (hazard ratio 0.22, 95% CI 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P=0.0078). Conclusion: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1. Citation Format: Marco Antonio Mascarella, Tolani Olonisakin, Purva Rumde, Varun Vendra, Melonie Nance, Seungwon Kim, Mark Kubik, Shaum Sridharan, Robert Ferris, Moon Fenton, Daniel Clayburgh, James Ohr, Malabika Sen, Sonali Joyce, James Herman, Jennifer Grandis, Dan Zandberg, Umamaheswar Duvvuri. Response to neoadjuvant targeted therapy in operable head and neck cancer confers survival benefit. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4338.
Abstract 4245: Effects of black raspberries extract on DNA repair capacity and metabolic activation/detoxification of the tobacco carcinogen dibenzo[<i>def,p</i>] in human oral cells
Authors: Yuan-Wan Sun, Kun-Ming Chen, Ana H. Sales, Nicholas Geacintov, Karam El-Bayoumy
Journal: Cancer Research (2023)

Abstract We previously reported that black raspberries (BRB) powder inhibits dibenzo[def,p]chrysene (also known as dibenzo[a,l]pyrene; DBP)-induced DNA damage, mutagenesis and carcinogenesis in the mouse oral cavity. The effects of BRB on the capacity of DNA repair was investigated in an established in vitro system using HeLa cells to assess the DNA repair capacity. We found that pre-treatment of Hela cells with BRB extracts (BRBE) can enhance the nucleotide excision repair (NER) of a bulky DNA adduct derived from the tobacco oral carcinogen benzo[a]pyrene by ~24% and this effect is correlated with the enhanced expressions of NER factors XPA and XPB. The NER activity of guanidinohydantoin (Gh), an oxidatively-derived non-bulky DNA lesion, is also enhanced by ~24%, while its base excision repair activity is enhanced by only ~6%. Using human oral leukoplakia (MSK-Leuk1) and oral squamous cell carcinoma SCC1483, we demonstrated that BRBE can inhibit DNA damage induced by DBP through the induction of GSH synthesis and enhancing GSH conjugates thereby inhibiting DNA damage. The effects of BRBE in MSK-Leuk1 and SCC1483 cells were further investigated on the DNA excision repair protein ERCC1 at 1, 6 and 24 h. ERCC1 forms the ERCC1-XPF enzyme complex that participates in several DNA repair pathways. Western blot analyses revealed that BRBE induced higher ERCC1 expression in SCC1483 than those observed in MSK-Leuk1 cells in a time-dependent manner. The results of our study demonstrate that BRBE is capable of inhibiting the metabolic activation, enhancing the detoxification pathway and DNA repair capacity which are consistent with its chemopreventive activity in vivo. Supported by NIH grant #CA173465. Citation Format: Yuan-Wan Sun, Kun-Ming Chen, Ana H. Sales, Nicholas Geacintov, Karam El-Bayoumy. Effects of black raspberries extract on DNA repair capacity and metabolic activation/detoxification of the tobacco carcinogen dibenzo[def,p] in human oral cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4245.
Abstract 3926: Activating missense mutations in ROS1 receptor harbor oncogenic potential and are sensitive to tyrosine kinase inhibition
Authors: Sudarshan R. Iyer, Kevin Nusser, Kristen Jones, Pushkar Shinde, Catherine Z. Beach, Clare Keddy, Erin Aguero, Jeremy Force, Ujwal Shinde, Monika A. Davare
Journal: Cancer Research (2023)

Abstract ROS1 encodes the largest receptor tyrosine kinase (RTK) in the human genome. Chromosomal rearrangements of the ROS1 gene generate oncogenic ROS1 fusion proteins that have been successfully targeted with tyrosine kinase inhibitors (TKIs), most notably in lung cancer. To date, ROS1 fusions are the only known biomarkers for therapeutic implementation of ROS1 TKIs. However, unlike known oncogenic mutations in EGFR and ALK RTKs, the functional impact of point mutations within the full-length ROS1 RTK is unknown. Here we queried the AACR Genie database, which consists of pan-cancer clinical genomic sequencing data from thousands of patient samples, for ROS1 aberrations and nominated thirty-four missense mutations residing in the ROS1 tyrosine kinase domain for functional interrogation. Immunoblotting revealed distinct impact of the mutations on kinase function, ranging from complete loss to significant increase in catalytic activity. Notably, Asp and Gly substitutions at the D2113 position within the ROS1 kinase domain dramatically increased autophosphorylation and activation of downstream signaling pathways. ROS1D2113N/G were found to be ROS1 TKI-sensitive transformative oncogenes in independent cell-based models. Molecular dynamic simulations of ROS1D2113N kinase revealed dramatic alterations in the activation loop of the mutant kinase as compared to wildtype. Global proteomics and phosphoproteomics showed that ROS1D2113N upregulates signaling via phosphorylation of known effectors (SHP2 and STAT3) similar to ROS1 fusions, but also upregulates other pathways, including mTORC2, JNK1/2, AP-1 and TGFB1. In vivo, ROS1D2113N drove tumor formation that was inhibited with ROS1 TKIs. Taken together, these data demonstrate for the first time that select point mutations within ROS1 drive tumorigenesis and can be therapeutically targetable with existing FDA-approved ROS1-TKIs. Citation Format: Sudarshan R. Iyer, Kevin Nusser, Kristen Jones, Pushkar Shinde, Catherine Z. Beach, Clare Keddy, Erin Aguero, Jeremy Force, Ujwal Shinde, Monika A. Davare. Activating missense mutations in ROS1 receptor harbor oncogenic potential and are sensitive to tyrosine kinase inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3926.
Abstract 3927: Genome-wide screening and validation of molecular targets and biomarkers for lung cancer
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Cancer Research (2023)

Abstract The number of lung cancer patients who respond well to currently available standard therapies is still small, new molecular targeted therapies with companion diagnostics are eagerly needed. We have been developing new molecular therapies targeting oncoproteins with their cancer biomarkers as follows, i) To identify strongly expressed genes in 120 lung cancers by genome-wide gene expression profile analysis, ii) To verify the candidate genes for their scarce expression in 23 normal organs, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering about 400 lung cancers (non-small cell lung cancers (NSCLCs) and SCLCs), iv) To examine their importance in the growth and/or invasion of cancer cells by siRNA, small molecule inhibitor, cell permeable peptides targeting their function and/or antibody assays, and v) To analyze the oncogenic function of the target molecules. By this system, we identified 50 oncoproteins and selected a LSERT (lung cancer-specific receptor tyrosine kinase) as a candidate. Immunocytochemical and immunohistochemical analyses confirmed that LSERT protein was expressed in cytoplasm and cytoplasmic membrane of lung cancer cells, but it was hardly expressed in normal lung cells. Strong LSERT expression was associated with poorer prognosis for surgically-treated NSCLC patients, and it was an independent prognostic factor. Exogenous expression of LSERT increased the cell growth and invasion probably through its elevated kinase activity and subsequent phosphorylation of downstream proteins. Inhibition of LSERT expression by siRNAs or treatment with anti-LSERT antibody suppressed the growth of lung cancer cells. Our genome-wide screening might be a useful approach to identify target molecules for developing new therapeutics and diagnostics. LSERT could be a candidate cancer biomarker and therapeutic target for lung cancer. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Genome-wide screening and validation of molecular targets and biomarkers for lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3927.
Abstract 4340: HLA-B44 motif neoepitope is associated with a favorable tumor immune microenvironment and predicts ICB response in NSCLC
Authors: Rui Li, Charlene M. Fares, Tristan R. Grogan, Tianhao Zhang, Debory Li, Matthew Theisen, Maria A. Velez, Paige M. Brodrick, Jackson P. Lind-Lebuffe, Yazeed Radwan, Gregory A. Ayzenberg, David Elashoff, Bin Liu, Aaron E. Lisberg, Amy L. Cumming, Edward B. Garon
Journal: Cancer Research (2023)

Abstract Immune check point blockade (ICB) has recently transformed the treatment of non-small cell lung (NSCLC). However, the majority of patients do not respond to ICB. For ICB to be effective, tumor neoantigens need to be presented in a human leukocyte antigen (HLA) class I-restricted manner. Recent studies by our group and others have shown that HLA-B44 supertype is associated with extended survival in patients treated with ICB. Herein, we hypothesize that HLA-B44-specific motif neoepitopes generate an active tumor immune microenvironment and a favorable ICB response in NSCLC. Utilizing the TCGA database, we found that nearly half of the NSCLC patients have at least one HLA-B44 allele, of whom 36.8% and 37.3% of patients harbor at least one B44 motif neoepitope in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC), respectively. In a pooled analysis of patients with LUAD and LUSC, gene expression of PD-L1, CTLA-4, LAG-3, CXCL9, CXCL10, CXCL13, CD8A and cytolytic gene signature (includes GZMA and PRF1) is elevated in patients with B44 motif neoepitopes compared to those without motif neoepitopes. Immune cell component analysis showed increased infiltration of Th1, Th2 and CD8 T cells in LUAD and regulatory and CD8 T cells in LUSC. Although a linear regression model revealed a positive correlation between tumor mutational burden (TMB) and number of B44 motif neoepitopes, pooled analysis of LUAD and LUSC with similar TMB showed significant elevation of CTLA-4, LAG3, CXCL10 and a trend of increased expression of CXCL9 in motif patients. Upon investigation of possible immune editing, we found a significantly higher proportion of genes containing B44 neoepitope downregulated at the RNA level both in LUAD and LUSC. Lastly, we showed that combining B44 motif with either PD-L1 or TMB improved prediction of progression-free survival in NSCLC patients treated with ICB. In summary, we demonstrate that HLA-B44 motif neoepitopes are associated with a favorable tumor immune microenvironment and can serve as a potential biomarker for ICB benefit in NSCLC patients. Citation Format: Rui Li, Charlene M. Fares, Tristan R. Grogan, Tianhao Zhang, Debory Li, Matthew Theisen, Maria A. Velez, Paige M. Brodrick, Jackson P. Lind-Lebuffe, Yazeed Radwan, Gregory A. Ayzenberg, David Elashoff, Bin Liu, Aaron E. Lisberg, Amy L. Cumming, Edward B. Garon. HLA-B44 motif neoepitope is associated with a favorable tumor immune microenvironment and predicts ICB response in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4340.
Abstract 4240: Tumor PD-L1 induction associated with dietary protein restriction is modulated by PERK activation
Authors: Ricardo Cordova, Sean Colligan, Chris Rupert, Ronald Wek, Kirk Staschke, Roberto Pili
Journal: Cancer Research (2023)

Abstract Tumor cells rely on the Integrated Stress Response (ISR) to adapt to different environmental and physiological stresses. The ISR is comprised of four eIF2 kinases that sense different stresses and catalyze phosphorylation of the alpha subunit of eIF2. This results in inhibition of global translation initiation, but at the same time results in preferential translation of select mRNA transcripts in order to relieve stress. Recent work has suggested that programmed death-ligand 1 (PD-L1), a cell surface protein commonly upregulated by tumors to evade the immune system, may be translationally regulated by the ISR in cancer. PD-L1 interaction with immune-checkpoint receptor programmed death-1 (PD-1) leads to the negative regulation of T cell activation and inhibitors that block the PD-L1/PD-1 interaction are widely used to treat different cancers. The ISR may serve as a novel therapeutic target to modulate PD-L1 protein levels and treat immune-evasive cancers. Our group has previously reported that dietary protein restriction increases the anti-tumor effect of PD-1 inhibition in the RENCA kidney cancer mouse model. Here, we show that in the RENCA model, phospho-PERK and phospho-eIF2α protein levels correlate with PD-L1 induction associated with dietary protein restriction. This is supported by TCGA data that shows a correlation between PERK and PD-L1 mRNA levels in different genitourinary cancers. In vitro, activation of the eIF2 kinases PERK and GCN2 by ER stress and amino acid starvation, respectively, in both RENCA cells and prostate cancer cells, leads to induction of PD-L1 protein without changing mRNA levels, suggesting preferential translation under stress conditions. Inhibiting PERK using selective inhibitors blocked ER stress-induced induction of PD-L1. These data support the notion that PD-L1 is induced by dietary protein restriction and is translationally regulated by the ISR. Modulating PD-L1 protein levels in immune-evasive tumors by targeting the ISR in the context of dietary protein restriction may enhance the anti-tumor response to immune checkpoint inhibitors. Citation Format: Ricardo Cordova, Sean Colligan, Chris Rupert, Ronald Wek, Kirk Staschke, Roberto Pili. Tumor PD-L1 induction associated with dietary protein restriction is modulated by PERK activation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4240.
Abstract 4175: Development of breast cancer risk assessment tool: The Korean decision aid for cancer screening (K-DACS) study
Authors: Wonyoung Jung, Yong-Moon Mark Park, Sang Hyun Park, Kyungdo Han, Junhee Park, Yohwan Yeo, Jung Kwon Lee, Dale P. Sandler, Dong Wook Shin
Journal: Cancer Research (2023)

Abstract Purpose: Widely used breast cancer risk prediction tools are based on data from Western countries, but risk factors may differ for Asian women. Hence, we aimed to develop a risk assessment tool for breast cancer in Asian women, using a nationwide, population-based cohort in Korea. Methods: Women aged ≥ 40 years who participated in both breast cancer screening and general health examination in 2009 were eligible for this study. Age, body mass index (BMI), breast density, lifestyle and reproductive factors, and comorbidities were used to develop 5-year breast cancer risk prediction models in premenopausal (n=771,856) and postmenopausal (n=1,108,047) women at baseline. Backward stepwise selection in the Cox proportional hazards model was used to construct the best-fit risk prediction model, which was then converted into a risk score nomogram, representing an individual probability estimate of incident breast cancer. Model performance was evaluated by discrimination and calibration. Results: Among premenopausal women, high BMI, low parity, short breastfeeding period, early age at menarche, high breast density, history of benign breast mass, and family history of breast cancer contributed to breast cancer risk prediction. The appropriate predictors in postmenopausal women additionally included age, type 2 diabetes, dyslipidemia, late age at menopause, hormone replacement therapy use, except for number of parities. The concordant statistic of risk prediction model was 0.58 (95% confidence interval [CI] 0.57-0.59) for premenopausal women, and 0.64 (95% CI 0.63-0.65) for postmenopausal women. Our model correlated well in the calibration plot in both premenopausal and postmenopausal women.Conclusions: Our breast cancer risk prediction model showed good performance for postmenopausal women, providing the background for risk-based screening recommendations in Asian women. Citation Format: Wonyoung Jung, Yong-Moon Mark Park, Sang Hyun Park, Kyungdo Han, Junhee Park, Yohwan Yeo, Jung Kwon Lee, Dale P. Sandler, Dong Wook Shin. Development of breast cancer risk assessment tool: The Korean decision aid for cancer screening (K-DACS) study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4175.
Abstract 3925: JunB regulates expression of HPV genes in head and neck cancer
Authors: Hina Rehmani, Travis P. Schrank, Natalia Issaeva, Wendell G. Yarbrough
Journal: Cancer Research (2023)

Abstract The incidence of HPV-positive head and neck squamous cell carcinoma (HNSCC) is now being considered an epidemic in the US and Western Europe as rates have surpassed those for cervical cancer. For approximately 14,400 patients per year in the US, initial therapy is aggressive and often results in adverse lifelong side effects such as difficulty swallowing and speaking. Despite having a higher cure rate than HPV-negative HNSCC, the recurrence rate is still approximately 30%. Therefore, new treatment options need to be available for these relapsed patients. Our lab was prompted to explore demethylation as a therapeutic option as HPV-positive HNSCC have a more hypermethylated genome than HPV-negative cancers. 5-azacytidine (5-aza) is a synthetic cytidine analog that causes DNA demethylation by trapping methyltransferases to chromatin; it is FDA-approved for the treatment of myelodysplasia and acute myeloid leukemia. Our lab found that low doses of 5-aza delayed HPV-positive xenograft tumor growth and that HPV-positive tumor samples from patients treated with 5-aza in a window trial had increased apoptosis. They also observed a marked downregulation of HPV gene expression after 5-aza. Decreased HPV E6 expression, followed by reactivation of tumor suppressor p53, induced p53-dependent apoptosis in HPV-positive HNSCC. To further explore the mechanism of this sensitivity to 5-Aza, we first determined that 5-aza regulates the transcription of HPV genes, but not the stability of HPV transcripts. We found that the transcriptional regulation of HPV genes after 5-aza depends on the proto-oncogene JunB, a component of the transcription factor Activator Protein 1 (AP-1). Additionally, silencing of JunB abolished the expression of HPV E6/E7 genes and reactivated tumor suppressor p53 in HPV-positive HNSCC. Furthermore, we revealed that clonogenic survival of HPV-positive head and neck cancer cells is dependent on JunB expression. Our study exposes an important component of 5-Aza-associated sensitivity and toxicity in HPV-positive HNSCC and identifies a novel dependency on JunB, potentially providing a new rational targeted therapy. Citation Format: Hina Rehmani, Travis P. Schrank, Natalia Issaeva, Wendell G. Yarbrough. JunB regulates expression of HPV genes in head and neck cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3925.